The hallmark of fibrotic disorders is a highly cross-linked and dense collagen matrix, a property driven by the oxidative action of lysyl oxidase. Other fibrosis-associated proteins also contribute to the final collagen matrix properties, one of which is fibromodulin - its interactions with collagen affect collagen cross-linking, packing, and fibril diameter. We investigated the possibility that a specific relationship exists between fibromodulin and lysyl oxidase, potentially imparting a specific collagen matrix phenotype. We mapped the fibromodulin-collagen interaction sites using the Collagen II and III Toolkit peptide libraries. Fibromodulin interacted with the peptides containing the known collagen cross-linking sites and the MMP-1... (More)

The hallmark of fibrotic disorders is a highly cross-linked and dense collagen matrix, a property driven by the oxidative action of lysyl oxidase. Other fibrosis-associated proteins also contribute to the final collagen matrix properties, one of which is fibromodulin - its interactions with collagen affect collagen cross-linking, packing, and fibril diameter. We investigated the possibility that a specific relationship exists between fibromodulin and lysyl oxidase, potentially imparting a specific collagen matrix phenotype. We mapped the fibromodulin-collagen interaction sites using the Collagen II and III Toolkit peptide libraries. Fibromodulin interacted with the peptides containing the known collagen cross-linking sites and the MMP-1 cleavage site in collagens I and II. Interestingly, the interaction sites are closely aligned within the quarter-staggered collagen fibril, suggesting a multivalent interaction between fibromodulin and several collagen helices. Furthermore, we detected an interaction between fibromodulin and lysyl oxidase - a major collagen cross-linking enzyme - and mapped the interaction site to 12 N-terminal amino acids on fibromodulin. This interaction also increases the activity of lysyl oxidase. Altogether, the data suggest a fibromodulin-modulated collagen cross-linking mechanism, where fibromodulin binds to a specific part of the collagen domain and also forms a complex together with lysyl oxidase, targeting the enzyme towards specific cross-linking sites. (Less)

@article{8233d566-ac64-4e2b-89a5-ef320ec420ec,
abstract = {The hallmark of fibrotic disorders is a highly cross-linked and dense collagen matrix, a property driven by the oxidative action of lysyl oxidase. Other fibrosis-associated proteins also contribute to the final collagen matrix properties, one of which is fibromodulin - its interactions with collagen affect collagen cross-linking, packing, and fibril diameter. We investigated the possibility that a specific relationship exists between fibromodulin and lysyl oxidase, potentially imparting a specific collagen matrix phenotype. We mapped the fibromodulin-collagen interaction sites using the Collagen II and III Toolkit peptide libraries. Fibromodulin interacted with the peptides containing the known collagen cross-linking sites and the MMP-1 cleavage site in collagens I and II. Interestingly, the interaction sites are closely aligned within the quarter-staggered collagen fibril, suggesting a multivalent interaction between fibromodulin and several collagen helices. Furthermore, we detected an interaction between fibromodulin and lysyl oxidase - a major collagen cross-linking enzyme - and mapped the interaction site to 12 N-terminal amino acids on fibromodulin. This interaction also increases the activity of lysyl oxidase. Altogether, the data suggest a fibromodulin-modulated collagen cross-linking mechanism, where fibromodulin binds to a specific part of the collagen domain and also forms a complex together with lysyl oxidase, targeting the enzyme towards specific cross-linking sites.},
author = {Kalamajski, Sebastian and Bihan, Dominique and Bonna, Arkadiusz and Rubin, Kristofer and Farndale, Richard W},
issn = {1083-351X},
language = {eng},
month = {02},
number = {15},
pages = {7951--79060},
publisher = {ASBMB},
series = {Journal of Biological Chemistry},
title = {Fibromodulin Interacts with Collagen Cross-linking Sites and Activates Lysyl Oxidase.},
url = {http://dx.doi.org/10.1074/jbc.M115.693408},
volume = {291},
year = {2016},
}